U.S. patent application number 12/316821 was filed with the patent office on 2009-06-18 for n-demethylation of n-methyl morphinans.
Invention is credited to David W. Berberich, Gary L. Cantrell, Tao Jiang, Peter X. Wang.
Application Number | 20090156815 12/316821 |
Document ID | / |
Family ID | 40386498 |
Filed Date | 2009-06-18 |
United States Patent
Application |
20090156815 |
Kind Code |
A1 |
Wang; Peter X. ; et
al. |
June 18, 2009 |
N-demethylation of N-methyl morphinans
Abstract
The present invention provides a synthetic process for the
N-demethylation of N-methyl morphinans. In particular, the
invention provides improved synthetic methods for the preparation
of N-demethylated morphinan compounds that may be employed as
starting materials, for example, commonly available N-methyl
opiates such as oripavine and thebaine, and C(3)-protected hydroxy
derivatives of oripavine.
Inventors: |
Wang; Peter X.; (Clarkson
Valley, MO) ; Jiang; Tao; (St. Louis, MO) ;
Cantrell; Gary L.; (Troy, IL) ; Berberich; David
W.; (St. Peters, MO) |
Correspondence
Address: |
Mallinckrodt Inc.
675 McDonnell Boulevard
HAZELWOOD
MO
63042
US
|
Family ID: |
40386498 |
Appl. No.: |
12/316821 |
Filed: |
December 17, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61014086 |
Dec 17, 2007 |
|
|
|
Current U.S.
Class: |
546/44 |
Current CPC
Class: |
A61P 25/04 20180101;
C07D 489/02 20130101 |
Class at
Publication: |
546/44 |
International
Class: |
C07D 489/02 20060101
C07D489/02 |
Claims
1. A process for preparing a compound comprising Formula 2 from a
compound comprising Formula 1 according to the following reaction:
##STR00014## wherein: R.sup.1 is selected from the group consisting
of hydrogen, hydrocarbyl, and substituted hydrocarbyl; R.sup.2,
R.sup.3, and R.sup.4 are independently selected from the group
consisting of hydrogen, halogen, hydroxyl, {--}OR.sup.8,
hydrocarbyl, and substituted hydrocarbyl; R.sup.6 is an atom
selected from the group consisting of oxygen and nitrogen; R.sup.8
is selected from the group consisting of hydrocarbyl and
substituted hydrocarbyl; L is halogen; Y is an atom selected from
the group consisting of oxygen, nitrogen and sulfur; Z is selected
from the group consisting of hydrocarbyl and substituted
hydrocarbyl; and n is 1 or 2.
2. The process of claim 1, wherein: R.sup.1 is selected from the
group consisting of hydrogen, alkyl, alkenyl, aryl, substituted
alkyl, substituted alkenyl, substituted aryl, acyl, alkoxycarbonyl,
acetal, ether, silyl ether, and alkylsulfonyl; R.sup.2, R.sup.3,
and R.sup.4 are independently selected from the group consisting of
hydrogen, halogen, hydroxyl, acyl, alkyl, alkenyl, aryl,
substituted alkyl, substituted alkenyl, substituted aryl, and
alkoxycarbonyl; L is selected from the group consisting of bromo
and chloro; Y is oxygen; and Z is selected from the group
consisting of alkyl, alkenyl, alkylaryl, aralkyl, aryl, substituted
alkyl, substituted alkenyl, substituted alkylaryl, substituted
aralkyl, and substituted aryl.
3. The process of claim 2, wherein R.sup.1 is selected from the
group consisting of hydrogen, methyl, alkyl, acyl, alkoxycarbonyl,
and alkylsulfonyl, and Z is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
phenyl, benzyl, methoxymethyl, vinyl, or 2-chloroethyl.
4. The process of claim 1, wherein R.sup.1 is selected from the
group consisting of hydrogen, methyl, and an oxygen protecting
group; Y is oxygen; R.sup.2, R.sup.3, and R.sup.4 are each
hydrogen; and Z is selected from the group consisting of alkyl and
benzyl.
5. The process of claim 4, wherein R.sup.6 is oxygen and n is
1.
6. The process of claim 4, wherein R.sup.6 is nitrogen and n is
2.
7. The process of claim 1, wherein LC(O)OZ is a
hydrocarbylhaloformate selected from the group consisting of a
C.sub.1-8 alkyl chloroformate, phenyl chloroformate, benzyl
chloroformate, and a combination thereof.
8. The process of claim 1, wherein C(O)NZ.sub.2 is a
N,N-dihydrocarbylformamide selected from the group consisting of
N,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylformamide,
N,N-dibutylformamide, N,N-diisobutylformamide, and a mixture
thereof.
9. The process of claim 1, wherein the molar ratio of LC(O)OZ or
C(O)NZ.sub.2 to the compound comprising Formula 1 is from about 1:1
to about 3:1; the proton acceptor has a pKa greater than about 7
and is selected from the group consisting of NaHCO.sub.3,
KHCO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOH, KOH, and
combinations thereof; and the molar ratio of the proton acceptor to
the compound comprising Formula 1 is from about 1.5:1 to about
6:1.
10. The process of claim 1 wherein the reaction is conducted in the
presence of a solvent system.
11. The process of claim 10, wherein the solvent system comprises
an organic solvent selected from the group consisting of benzene,
chloroform, diethyl ether, ethyl acetate, n-propyl acetate,
heptane, hexane, toluene, and a combination thereof; and the molar
ratio of organic solvent to the compound comprising Formula 1 is
from about 0.5:1 to about 20:1.
12. The process of claim 11, wherein the solvent system further
comprises a protic solvent selected from the group consisting of
water, methanol, ethanol, isopropyl alcohol, isobutyl alcohol,
t-butyl alcohol, n-propyl alcohol, n-butyl alcohol, and a
combination thereof.
13. The process of claim 11, wherein the solvent system further
comprises a water-miscible solvent selected from the group
consisting of water, acetonitrile, 1-methyl-2-pyrrolidinone,
N,N-dimethylacetamide, N,N-formamide, acetone, tetrahydrofuran, and
a combination thereof.
14. The process of claim 1, wherein the reaction is conducted at a
temperature ranging from about 0.degree. C. to about 40.degree.
C.
15. The process of claim 1, wherein the yield of the compound
comprising Formula 2 is from about 65% to about 95%.
16. The process of claim 1, wherein the optical activity of
compounds comprising Formulas 1 and 2 is selected from the group
consisting of (-) enantiomer, (+) enantiomer, and a combination
thereof.
17. The process of claim 1, wherein the configuration of carbons 5,
13, 14, and 9, respectively, of compounds comprising Formulas 1 and
2 is selected from the group consisting RRRS, RRSS, SRRS, SRSS,
RSRR, RSSR, SSRR, and SSSR.
18. An N-carboxylic acid ester morphinan derivative comprising
Formula 2: ##STR00015## wherein R.sub.3 is selected from the group
consisting of methyl, --C(O)OZ, and a hydroxy protecting group, and
Z is selected from the group consisting of hydrocarbyl and
substituted hydrocarbyl.
19. The N-carboxylic acid ester morphinan derivative of claim 18,
wherein Z is selected from the group consisting of methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl,
methoxymethyl, vinyl, and 2-chloroethyl.
20. The N-carboxylic acid ester morphinan derivative of claim 18,
wherein R.sub.3 is --C(O)OZ and Z is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, phenyl, benzyl, methoxymethyl, vinyl, and
2-chloroethyl.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority from Provisional
Application Ser. No. 61/014,086 filed on Dec. 17, 2007, which is
hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention generally relates to the
N-demethylation of N-methyl morphinans.
BACKGROUND OF THE INVENTION
[0003] Commercially valuable "nal" morphinan compounds or
intermediates, such as naltrexone, naloxone, nalbuphene, nalmefene,
and buprenorphine, are generally prepared from nor-morphinan
compounds that lack substitution on the nitrogen atom of the
heterocyclic ring. These nor-morphinan compounds may be derived
from natural opiates or derivatives, such as thebaine and
oripavine. This approach, however, requires removal of the N-methyl
substituent, an approach that can lead to a complex mixture of
products. There is a need, therefore, for improved synthetic
methods for the preparation of N-demethylated morphinan
compounds.
SUMMARY OF THE INVENTION
[0004] Among the various aspects of the present invention may be
noted the provision of improved synthetic methods for the
preparation of N-demethylated morphinan compounds that may employ
as starting materials, for example, commonly available N-methyl
opiates such as oripavine and thebaine, and C(3)-protected hydroxy
derivatives of oripavine.
[0005] One aspect of the invention encompasses a process for
preparing a compound comprising Formula 2 from a compound
comprising Formula 1 according to the following reaction:
##STR00001##
[0006] wherein: [0007] R.sup.1 is selected from the group
consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;
[0008] R.sup.2, R.sup.3, and R.sup.4 are independently selected
from the group consisting of hydrogen, halogen, hydroxyl,
{--}OR.sup.8, hydrocarbyl, and substituted hydrocarbyl; [0009]
R.sup.6 is an atom selected from the group consisting of oxygen and
nitrogen; [0010] R.sup.8 is selected from the group consisting of
hydrocarbyl and substituted hydrocarbyl; [0011] L is halogen;
[0012] Y is an atom selected from the group consisting of oxygen,
nitrogen and sulfur; [0013] Z is selected from the group consisting
of hydrocarbyl and substituted hydrocarbyl; and [0014] n is 1 or
2.
[0015] A further aspect of the invention provides an N-carboxylic
acid ester morphinan derivative comprising Formula 2:
##STR00002##
[0016] wherein: [0017] R.sub.3 is selected from the group
consisting of methyl, -C(O)OZ, and a hydroxy protecting group, and
[0018] Z is selected from the group consisting of hydrocarbyl and
substituted hydrocarbyl.
[0019] Other aspects and iterations of the invention are described
in more detail below.
DETAILED DESCRIPTION OF THE INVENTION
[0020] A process has been discovered for the N-demethylation of a
variety of N-methyl morphinan compounds. In particular, the process
comprises replacing the N-methyl substituent of an N-methyl
morphinan substrate with a carboxylic acid ester substituent or a
carboamide substituent to form an N-carboxylic acid ester morphinan
derivative or an N-carboamide morphinan derivative, respectively.
The resulting N-carboxylic acid ester or N-carboamide derivative
may then be converted to yield other morphinan derivatives such as,
for example, the opiate antagonist, naltrexone or naloxone.
I. N-Demethylation Reaction
[0021] For purposes of illustration, Reaction Scheme 1 depicts the
N-demethylation of N-methyl morphinan substrate (1) and the
formation of an N-substituted morphinan derivative (2) in
accordance with one aspect of the present invention:
##STR00003##
[0022] wherein: [0023] R.sup.1 is selected from the group
consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;
[0024] R.sup.2, R.sup.3, and R.sup.4 are independently selected
from the group consisting of hydrogen, halogen, hydroxyl,
{--}OR.sup.8, hydrocarbyl, and substituted hydrocarbyl; [0025]
R.sup.6 is an atom selected from the group consisting of oxygen and
nitrogen; [0026] R.sup.8 is selected from the group consisting of
hydrocarbyl and substituted hydrocarbyl; [0027] L is halogen;
[0028] Y is an atom selected from the group consisting of oxygen,
nitrogen, and sulfur; [0029] Z is selected from the group
consisting of hydrocarbyl and substituted hydrocarbyl; and [0030] n
is 1 or 2.
[0031] In a preferred embodiment, the substituents of Reaction
Scheme 1 comprise: [0032] R.sup.1 is selected from the group
consisting of hydrogen, alkyl, alkenyl, aryl, substituted alkyl,
substituted alkenyl, substituted aryl, acyl, alkoxycarbonyl,
acetal, ether, silyl ether, and alkylsulfonyl; [0033] R.sup.2,
R.sup.3, and R.sup.4 are independently selected from the group
consisting of hydrogen, halogen, hydroxyl, acyl, alkyl, alkenyl,
aryl, substituted alkyl, substituted alkenyl, substituted aryl, and
alkoxycarbonyl; [0034] R.sup.6 is selected from the group
consisting of oxygen and nitrogen; [0035] L is selected from the
group consisting of chloro and bromo; [0036] Y is oxygen; [0037] Z
is selected from the group consisting of alkyl, alkenyl, alkylaryl,
aralkyl, aryl, substituted alkyl, substituted alkenyl, substituted
alkylaryl, substituted aralkyl, and substituted aryl; and [0038] n
is 1 or 2.
[0039] In a further iteration of this embodiment, R.sup.1 is
selected from the group consisting of hydrogen, methyl, alkyl,
acyl, alkoxycarbonyl, and alkylsulfonyl. In an exemplary iteration
of this embodiment, Z is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
phenyl, benzyl, methoxymethyl, vinyl, and 2-chloroethyl.
[0040] The process of the invention comprises treating an N-methyl
morphinan substrate (compound 1) with a demethylating agent to form
an N-substituted morphinan (compound 2). In general, the substrate
for the N-demethylation reaction (compound 1) may be any N-methyl
morphinan compound. In preferred embodiments, compound 1 may be
thebaine, oripavine, or a derivative of each of these compounds.
When compound 1 comprises thebaine, R.sup.1 is methyl, R.sup.2,
R.sup.3, and R.sup.4 are each hydrogen, and Y is oxygen.
Alternatively, when compound 1 comprises oripavine, R.sup.1 is
hydrogen, R.sup.2, R.sup.3, and R.sup.4 are each hydrogen, and Y is
oxygen. One of skill in the art will appreciate that the oxygen
attached to C(3) of oripavine or another N-methyl morphinan
substrate may be protected with an oxygen protecting group.
[0041] The oxygen protecting group may be alkoxycarbonyl, acyl,
acetal, ether, ester, silyl ether, alkylsulfonyl, or arylsulfonyl.
Exemplary oxygen protecting groups include allyl, triphenylmethyl
(trityl or Tr), benzyl, methanesulfonyl, p-toluenesulfonyl,
p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), methoxymethyl (MOM),
p-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl
(EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP),
2-trimethylsilylethoxymethyl (SEM), benzoate (Bz), allyl carbonate,
2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl
carbonate, trimethylsilyl (TMS), triethylsilyl (TES),
triisopropylsilyl (TIPS), triphenylsilyl (TPS),
t-butyldimethylsilyl (TBDMS), and t-butyldiphenylsilyl (TBDPS). A
variety of protecting groups for the oxygen and the synthesis
thereof may be found in "Protective Groups in Organic Synthesis" by
T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999.
[0042] In the process, compound 1 is contacted with a demethylating
agent. In general, the demethylating agent may be a
hydrocarbylhaloformate or a N,N-dihydrocarbylformamide. Mixtures of
hydrocarbylhaloformates or mixtures of
N,N-dihydrocarbylhaloformamides and at least one
hydrocarbylhaloformate may also be employed.
[0043] In one embodiment, the N-demethylating agent may be a
hydrocarbylhaloformate having the formula LC(O)OZ, wherein L and Z
are as defined above. In a preferred embodiment utilizing a
hydrocarbylhaloformate demethylating agent, L may be chloro or
bromo and Z may be methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, phenyl, benzyl, methoxymethyl, vinyl, or
2-chloroethyl. In an exemplary embodiment, the
hydrocarbylhaloformate may be a C.sub.1-8 alkyl chloroformates
(e.g., C.sub.1 to C.sub.8 alkyl), phenyl chloroformate, benzyl
chloroformate, or a combination thereof.
[0044] In another embodiment, the demethylating agent may be a
N,N-dihydrocarbylformamide having the formula C(O)NZ.sub.2, Z is as
defined above. In an exemplary embodiment, the
N,N-dihydrocarbylformamide may be N,N-dimethylformamide,
N,N-diethylformamide, N,N-dipropylformamide, N,N-dibutylformamide,
N,N-diisobutylformamide, and the like.
[0045] To minimize the formation of byproducts, the demethylating
agent is preferably maintained in relatively low concentration
relative to the N-methyl morphinan substrate. In a batch reaction,
for example, this can be achieved by incremental addition of the
N-demethylating agent to a reaction mixture containing the N-methyl
morphinan substrate. Regardless of whether the reaction is carried
out in a batch, continuous, or semi-continuous mode, it is
generally preferred that the reaction mixture contain less than
about 1 equivalent to about 3 equivalents of the demethylating
agent for each equivalent of the N-methyl morphinan substrate.
[0046] To facilitate the N-demethylation of the N-methyl morphinan
substrate, the reaction is typically carried out in the presence of
a proton acceptor. In general, the proton acceptor has a pKa of
between about 7 and about 13, preferably between about 8 and about
10. Representative proton acceptors that may be employed include,
but are not limited to, borate salts (such as, for example,
Na.sub.3BO.sub.3), di- and tri-basic phosphate salts (such as, for
example, Na.sub.2HPO.sub.4 and Na.sub.3PO.sub.4), bicarbonate salts
(such as, for example, NaHCO.sub.3, KHCO.sub.3, mixtures thereof,
and the like), hydroxide salts (such as, for example, NaOH, KOH,
mixtures thereof, and the like), carbonate salts (such as, for
example, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, mixtures thereof, and
the like), organic bases (such as, for example, pyridine,
triethylamine, diisopropylethylamine, N-methylmorpholine,
N,N-dimethylaminopyridine, and mixtures thereof), organic buffers
(such as, for example, N-(2-acetamido)-2-aminoethane sulfonic acid
(ACES), N-(2-acetamido)-iminodiacetic acid (ADA),
N,N-bis(2-hydroxyethyl)glycine (BICINE),
3-(cyclohexylamino)-1-propanesulfonic acid (CAPS),
2-(cyclohexylamino) ethanesulfonic acid (CHES),
4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS),
4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES),
2-(4-morpholinyl)ethanesulfonic acid (MES),
4-morpholinepropanesulfonic acid (MOPS),
1,4-piperazinediethanesulfonic acid (PIPES), [(2-hydroxy-1,1
-bis(hydroxymethyl)ethyl)amino]-1 -propanesulfonic acid (TAPS),
2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid
(TES), salts and/or mixtures thereof, and the like), and
combinations thereof. Where the proton acceptor is an organic
buffer, the organic buffer preferably lacks a hydroxy-substituted
nitrogen atom, as this substituent may compete for reaction with a
hydrocarbylhaloformate reactant. In one embodiment, the proton
acceptor is selected from the group consisting of NaHCO.sub.3,
KHCO.sub.3, K.sub.2CO.sub.3, NaOH, KOH, and mixtures thereof. In a
preferred embodiment, the proton acceptor is NaHCO.sub.3,
KHCO.sub.3, or a combination thereof.
[0047] To enable the reaction to proceed at a commercially
desirable rate, it is generally preferred that the reaction mixture
contain at least about 1 equivalent of proton acceptor for each
equivalent of the N-methyl morphinan substrate. In a preferred
embodiment, the reaction mixture contains about 1.5 equivalents to
about 6 equivalents of proton acceptor per equivalent of N-methyl
morphinan substrate. In one particularly preferred embodiment, the
reaction mixture contains about 1.5 equivalents to about 3
equivalents of sodium or potassium bicarbonate, or a combined
mixture thereof, per equivalent of N-methyl morphinan
substrate.
[0048] The solvent system for the N-demethylation reaction
preferably includes an organic solvent. Representative organic
solvents include, but are not limited to, alkane and substituted
alkane solvents (including cycloalkanes), aromatic hydrocarbons,
esters, ethers, ketones, combinations thereof, and the like.
Specific organic solvents that may be employed, include, for
example, acetonitrile, benzene, butyl acetate, t-butyl methylether,
t-butyl methylketone, chlorobenzene, chloroform, dichloromethane,
cyclohexane, dichloromethane, dichloroethane, diethyl ether, ethyl
acetate, fluorobenzene, heptane, hexanes, isobutylmethylketone,
isopropyl acetate, methylethylketone, methyltetrahydrofuran, pentyl
acetate, n-propyl acetate, tetrahydrofuran, toluene, combinations
thereof, and the like. In an exemplary embodiment, the organic
solvent may be benzene, chloroform, diethyl ether, ethyl acetate,
n-propyl acetate, heptane, hexane, and/or toluene.
[0049] In addition to the organic solvent, the solvent system may
additionally contain a protic solvent, whereby the solvent system
is a two phase, organic phase/protic phase solvent system. Where a
two phase, organic/protic solvent system is employed, the solvent
system preferably includes water as a protic solvent. In general,
water tends to suppress the formation of unwanted side products in
the N-demethylation reaction. The solvent may alternatively, or
additionally, comprise other protic solvents such as alcohol or
other water-miscible solvent; thus, for example, the protic solvent
phase may be water, a water/alcohol mixture, or a
water/water-miscible solvent mixture. Representative alcohols for
the water/alcohol mixture include, for example, methanol, ethanol,
isopropyl alcohol, isobutyl alcohol, t-butyl alcohol, n-propyl
alcohol, n-butyl alcohol, and combinations thereof. Other
water-miscible solvents for the water/water-miscible solvent
mixture include, for example, acetonitrile,
1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-formamide,
acetone, tetrahydrofuran, and combinations thereof.
[0050] In general, the amount of organic solvent in the solvent
system is sufficient to solubilize the N-methyl morphinan
substrate, resulting in a substantially homogeneous reaction
mixture. The reaction mixture typically includes from about 0.5
equivalents to about 20 equivalents of the organic solvent for each
equivalent of the N-methyl morphinan substrate, preferably from
about 1 equivalent to about 5 equivalents. Where a two-phase system
is employed including water, the water generally occupies from
about 0.1 % to about 50% of the total reaction volume, preferably
from about 1% to about 20%. If present in combination with water,
the volume of alcohol or water-miscible solvent is generally from
about 0.05% to about 50% of the volume of water, preferably from
about 1% to about 10%.
[0051] To form the reaction mixture, the N-methyl morphinan
substrate is typically combined with the organic solvent (or the
two-phase solvent system) prior to the addition of the
N-demethylation agent and the proton acceptor. Alternatively,
however, the solvent(s), the N-demethylation agent, and the proton
acceptor may be combined and thereafter added to the reaction
vessel containing the N-methyl morphinan substrate.
[0052] The temperature of the reaction mixture for the
N-demethylation reaction will typically be within the range of
about -40.degree. C. to about 85.degree. C. More typically, the
reaction will be carried out at a temperature between about
-25.degree. C. and about 65.degree. C. Still more typically, the
reaction will be carried out at a temperature of about -20.degree.
C. and to about 40.degree. C. In one preferred embodiment, the
reaction is carried out at a temperature between about -15.degree.
C. and about 40.degree. C., for example, between 0.degree. C. and
40.degree. C. The reaction is typically performed under pressure,
and preferably in an inert atmosphere (e.g., nitrogen or
argon).
[0053] Typically, the reaction is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). In this context, a
"completed reaction" generally means that the reaction mixture
contains a significantly diminished amount of the substrate, and a
significantly increased amount of product compared to the amounts
of each present at the beginning of the reaction. In general, the
reaction proceeds for about 1 hour to about 24 hours, and more
typically, for about 2 hours to about 8 hours.
[0054] The N-substituted morphinan product (compound 2) may be an
N-carboxylic acid ester morphinan compound, wherein R.sup.6 is
oxygen and n is 1. Alternatively, the N-substituted morphinan
product (compound 2) may be an N-carboamide morphinan compound,
wherein R.sup.6 is nitrogen and n is 2. Compound 2 may be isolated
from the reaction mixture by methods known in the art, i.e., for
example, by filtration and/or centrifugation. The purity of
compound 2 is typically at least 90% as determined by
chromatography (e.g., HPLC). In exemplary embodiments, the purity
of compound 3 is at least 95%, at least 96%, at least 97%, at least
98%, at least 99%, or greater than 99.5% as determined by
chromatography. The yield of compound 2 may range from about 65% to
about 95% (mol/mol).
[0055] The process described herein may be used to produce a
N-substituted morphinan compound that has a (-) or (+)
stereochemistry configuration, with respect to the rotation of
polarized light. In one embodiment, therefore, the N-methyl
morphinan substrate corresponds to formula 1(-) and the
N-substituted morphinan product corresponds to formula 2(-):
##STR00004##
[0056] wherein n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, and
Z are as described above.
[0057] In another embodiment, the N-methyl morphinan substrate
corresponds to formula 1(+) and the N-substituted morphinan product
corresponds to formula 2(+):
##STR00005##
[0058] wherein n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, and
Z are as described above.
[0059] In yet another embodiment, the N-methyl morphinan substrate
and the N- substituted morphinan product may be an enantiomeric
mixture of the respective (-) and (+) enantiomers.
[0060] Furthermore, each chiral center of the compounds may have an
R or an S configuration. For ease of discussion, the ring atoms of
the core morphinan structure referenced herein are numbered as
follows:
[0061] As illustrated in the core morphinan structure, there are
four chiral carbons comprising any of the compounds utilized in the
process of the invention, i.e., carbons 5, 13, 14, and 9. Thus, the
configuration of the N-methyl morphinan substrate and the
N-substituted morphinan product may be RRRS, RRSS, SRRS, SRSS,
##STR00006##
RSRR, RSSR, SSRR, or SSSR, with respect to C(5), C(13), C(14), and
C(9). In an exemplary embodiment, the configuration of N-methyl
morphinan substrate and the N-substituted morphinan product may be
(-)RSRR or (+)SRSS.
II. Further Derivatization
[0062] The N-substituted morphinan products of the present
invention may be end products themselves, or intermediates that may
be further derivatized in one or more steps to yield further
morphinan intermediates or end products. For instance, the
N-carboxylic acid ester morphinan compound may be subsequently
converted to commonly utilized nor-morphinan intermediates, such as
noroxymorphone and noroxycodone which, in turn, may be further
derivatized to form other commercially valuable morphinan compounds
(e.g., buprenorphine, dihydroetorphine, diprenorphine, etorphine,
nalbuphene, nalmefene, naloxone, and naltrexone. General reaction
schemes for the preparation of such commercially valuable
morphinans are disclosed, among other places, in U.S. Pat. No.
4,368,326 to Rice, the entire disclosure of which is hereby
incorporated by reference herein. As previously described, the
N-carboxylic acid ester morphinan product used as a starting
material for this further derivatization may be the (-) enantiomer,
the (+) enantiomer, or an enantiomeric mixture of the two.
[0063] For purposes of illustration, Reaction Scheme 2 depicts the
preparation of noroxymorphone (9) from N-carboxylic acid ester
nororipavine (7) and Reaction Scheme 3 depicts the preparation of
noroxycodone (10) from N-carboxylic acid ester northebaine (4),
wherein R.sub.311 is an oxygen protecting group and Z is as defined
above in connection with Reaction Scheme 1.
##STR00007##
##STR00008##
[0064] As shown in Reaction Schemes 2 and 3, Step A involves the
oxidation of the N-carboxylic acid ester odpavine (7) or
N-carboxylic acid ester northebaine (4) to form an
.alpha.,.beta.-unsaturated morphinan-6-one (8) or (8A). In general,
the oxidation involves the treatment of the N-carboxylic acid ester
oripavine (7) or N-carboxylic acid ester northebaine (4) with an
oxidizing agent. A variety of oxidizing agents may be used in this
step for the oxidation of the C(6) and the C(14) positions of the
N-carboxylic acid ester oripavine (7) or N-carboxylic acid ester
northebaine (4). Examples of oxidizing agents that may be used
include, but are not limited to, dichromates (e.g., ammonium
dichromate, potassium dichromate, sodium dichromate, and the like);
bromates (e.g., barium bromate, magnesium bromate, potassium
bromate, sodium bromate, and the like); chlorates (e.g., ammonium
chlorate, barium chlorate, calcium chlorate, potassium chlorate,
sodium chlorate, and the like); chlorates (e.g., copper chlorite,
lead chlorite, potassium chlorite, sodium chlorite, and the like);
chloroisocyanuric acids (e.g., trichloroisocyanuric acid, and the
like); chromates (e.g., potassium chromate, and the like); chromium
oxides (e.g., chromic anhydride (chromium trioxide)); dichromates
(e.g., sodium dichromate, potassium dichromate, and the like);
hydrogen peroxide; hypobromites (e.g., sodium hypobromite, and the
like); hypochlorites (e.g., calcium hypochlorite, potassium
hypochlorite, sodium hypochlorite, and the like); hypoiodites
(e.g., sodium hypoiodite, potassium hypoiodite, and the like);
inorganic peroxides (e.g., barium peroxide, calcium peroxide,
cesium peroxide, lithium peroxide, magnesium peroxide, potassium
peroxide, rubidium peroxide, sodium peroxide, strontium peroxide,
and the like); iodates (e.g., calcium iodate, potassium iodate,
sodium iodate, zinc iodate, and the like); iodine oxides (e.g.,
diiodine pentaoxide, and the like); lead oxides (e.g., lead dioxde,
and the like); manganese dioxide; nitrates (e.g., ammonium nitrate,
ammonium cerium nitrate, barium nitrate, potassium nitrate, silver
nitrate, sodium nitrate, and the like); nitric acid; nitrites
(e.g., potassium nitrite, sodium nitrite, and the like);
perchlorates (e.g., ammonium perchlorate, potassium perchlorate,
sodium perchlorate, and the like); periodates (e.g., potassium
periodate, sodium periodate, and the like); periodic acids (e.g.,
metaperiodic acid, and the like); permanganates (e.g., ammonium
permanganate, magnesium permanganate, potassium permanganate,
sodium permanganate, and the like); peroxoborates (e.g., ammonium
peroxoborate, and the like); perchloric acid; peroxodisulfates
(e.g., ammonium peroxodisulfates, potassium peroxydisulfate, and
the like); peroxyacids (e.g., peroxyacetic acid, peroxybenzoic
acid, peroxyformic acid, trifluoroperacetic acid, and the like);
organic peroxides (e.g., benzoyl peroxide, and the like);
tetroxides (e.g., osmium tetroxide, ruthenium tetroxide, and the
like); and oxygen. As the oxygen source, air may also be used-. In
one particular embodiment, the oxidizing agent is a peroxyacid;
thus, for example, the oxidizing agent may be peroxyacetic acid,
peroxybenzoic acid, peroxyformic acid, or trifluoroperacetic acid.
Typically, a slight excess of the oxidizing agent is employed.
[0065] In Step B of Reaction Schemes 2 and 3, the
.alpha.,.beta.-unsaturated morphinan-6-one (8) or (8A) is reduced
to form compound 8R or compound 8AR, respectively. Generally, the
reduction is carried out to reduce the .alpha.,.beta.-unsaturation
between the C(7) and the C(8) ring carbon atoms and to remove the
carboxylic acid ester moiety (--C(O)OZ) from the nitrogen atom.
Depending on the particular substituents, i.e., depending upon the
nature of R.sub.311 and Z, additional treatment of the compound
with a hydrolyzing agent may be performed to remove the hydroxy
protecting group, R.sub.311, and the carboxylic acid ester moiety,
--C(O)OZ.
[0066] A wide variety of reducing approaches may be employed in
Step B including, for example, chemical reduction, catalytic
reduction, and the like. Representative reducing agents for use in
chemical reduction include hydrides (e.g., hydrogen iodide,
hydrogen sulfide, lithium aluminum hydride, sodium borohydride,
sodium cyanoborohydride, and the like), or combinations of a metal
(e.g., tin, zinc, or iron) or a metal compound (e.g., chromium
chloride, chromium acetate, and the like) with an organic or
inorganic acid (e.g., formic acid, acetic acid, propionic acid,
trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,
and the like), samarium iodide, and others. Representative reducing
agents for use in catalytic reduction methods with hydrogen include
commonly used catalysts such as, for example, platinum catalysts
(e.g., platinum black, colloidal platinum, platinum oxide, platinum
plate, platinum sponge, platinum wire, and the like), palladium
catalysts (e.g., palladium black, palladium on barium carbonate,
palladium on barium sulfate, colloidal palladium, palladium on
carbon, palladium hydroxide on carbon, palladium oxide, palladium
sponge, and the like), nickel catalysts (e.g., nickel oxide, Raney
nickel, reduced nickel, and the like), cobalt catalysts (e.g.,
Raney cobalt, reduced cobalt, and the like), iron catalysts (e.g.,
Raney iron, reduced iron, Ullmann iron, and the like), and others.
In one particular embodiment, the .alpha.,.beta.-unsaturated
morphinan-6-one (8) or (8A) is reduced using catalytic reduction
(e.g., Pd/C catalyzed transfer hydrogenation).
[0067] Step C of Reaction Schemes 2 and 3 involves a hydrolysis
reaction to form noroxymorphone (9) or noroxycodone (10). Where a
hydrolyzing agent is used to assist in the removal of the hydroxy
protecting group, R.sub.311, and/or the carboxylic acid ester
moiety, --C(O)OZ, a variety of aqueous hydrolyzing agents may be
employed, provided the particular hydrolyzing agent selected does
not affect any other positions or bonds present on the morphinan.
In general, conventional hydrolyzing agents may be employed, such
as sulfuric acid, phosphoric acid, methanesulfonic acid,
trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid,
trifluoromethanesulfonic acid, hydrochloric acid, or hydrobromic
acid.
[0068] Those of skill in the art will appreciate that other
N-substituted morphinan products may be derivatized to other
intermediate or end products using Steps A, B, and C, as outlined
above in Reaction Schemes 2 and 3, or using other derivatization
methods known in the art.
[0069] Other end product and intermediate morphinans of interest
that may be derived from N-carboxylic acid ester morphinan products
from Reaction Scheme 1 include a wide range of opiate receptor
agonists and antagonists, and intermediates thereof, generally
corresponding to Formula (100):
##STR00009##
[0070] wherein -A.sub.6-A.sub.7-A.sub.8-A.sub.14- corresponds to
Formulae (S), (T), (U), (V), (W), (X), (Y), or (Z):
##STR00010## ##STR00011##
[0071] wherein: [0072] R.sub.11 and R.sub.22 are independently
hydrogen, substituted and unsubstituted acyl, alkenyl, alkoxy,
alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl,
arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl, carboxyalkyl,
carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkylether, halo, haloalkoxy, haloalkyl, heteroaryl,
heterocyclic, hydroxyalkyl, hydroxy, protected hydroxy, or nitro;
[0073] R.sub.14 is hydrogen, acyloxy, hydroxy, protected hydroxy,
or together with R.sub.62 or R.sub.63 forms an ethylene bridge;
[0074] R.sub.17 is hydrogen, alkyl, alkoxy, alkylenecycloalkyl,
allyl, alkenyl, acyl, formyl, formyl ester, formamide, or benzyl;
[0075] R.sub.17a and R.sub.17b are independently hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, or benzyl; [0076] R.sub.18 and
R.sub.19 are independently hydrogen, substituted and unsubstituted
acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, arylthio,
alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy,
carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl,
cycloalkyl, cycloalkylalkyl, halo, haloalkoxy, haloalkyl,
heteroaryl, heterocyclic, hydroxyalkyl, hydroxy, or nitro, or
R.sub.18 and R.sub.19 together form keto;
[0077] R.sub.33 is alkoxy, acyloxy, hydroxy, or protected
hydroxy;
[0078] R.sub.61 is alkoxy, acyloxy, hydroxy, or protected
hydroxy;
[0079] R.sub.62 and R.sub.63 are independently hydrogen, alkyl,
alkenyl, alkynyl, allyl, alkoxy, alkylthio, acyloxy, or aryl,
together form keto, together with the carbon atom to which they are
attached form a ketal, dithioketal, or monoketal, or one of
R.sub.62 and R.sub.63, together with R.sub.14, forms an ethylene
bridge;
[0080] R.sub.71 and R.sub.81 are independently hydrogen,
hydrocarbyl, substituted hydrocarbyl, or halo; and
[0081] X is oxygen, sulfur, --S(O)--, --S(O.sub.2)--,
--C(R.sub.18)(R.sub.19)--, --N(R.sub.17)--, or
--N.sup.+(R.sup.17aR.sup.17b)--.
[0082] In a particular embodiment, the products and intermediates
produced according to the present invention are useful in the
preparation of a morphinan compound corresponding to Formula (100)
wherein X is --N(R.sub.17)-- or --N(R.sup.17aR.sub.17b)--, and
R.sub.17, R.sub.17a, and R.sub.17b, if present, are defined as
above.
[0083] For purposes of clarity, the carbon atoms of Formulae (S),
(T), (U), (V), (W), (X), (Y), and (Z) corresponding to A.sub.6,
A.sub.7, A.sub.8, and A.sub.14 of Formula (100), respectively, have
been identified (by indicating with an arrow which carbon atom
corresponds to each). Further, wavy lines have been included in
Formulae (S), (T), (U), (V), (W), (X), (Y), and (Z) to indicate the
points of attachment to the polycyclic ring of Formula (100).
[0084] As previously noted in connection with Reaction Schemes 2
and 3, exemplary intermediate morphinans that may be produced
include, for example, noroxymorphone (i.e., Formula (100) wherein
R.sub.11, R.sub.17, and R.sub.22 are hydrogen, R.sub.33 is hydroxy,
X is --N(R.sub.17)--, and -A.sub.6-A.sub.7-A.sub.8-A.sub.14-
corresponds t Formula (Y) wherein R.sub.14 is hydroxy, R.sub.62 and
R.sub.63 together form keto, and R.sub.7, and R.sub.8, are
hydrogen) (which corresponds to Formula (101) below) and
noroxycodone (i.e., Formula (100) wherein R.sub.11, R.sub.17, and
R.sub.22 are hydrogen, R.sub.33 is methoxy, X is --N(R.sub.17)--,
and -A.sub.6-A.sub.7-A.sub.8-A.sub.14- corresponds to Formula (Y)
wherein R.sub.14 is hydroxy, R.sub.62 and R.sub.63 together form
keto, and R.sub.71 and R.sub.81 are hydrogen) (which corresponds to
Formula (102) below), and salts, intermediates, and analogs
thereof.
[0085] Exemplary end product morphinans that may be derived from
noroxymorphone, noroxycodone, or otherwise from N-carboxylic acid
ester morphinan (2) of Reaction Scheme 1 include, for example,
nalbuphine, nalmefene, naloxone, naltrexone, naltrexone
methobromide, 3-0-methyl naltrexone, and the salts, intermediates,
and analogs thereof. Exemplary examples are presented below:
##STR00012## ##STR00013##
Definitions
[0086] The term "acyl," as used herein alone or as part of another
group, denotes the moiety formed by removal of the hydroxy group
from the group COOH of an organic carboxylic acid, e.g., RC(O)--,
wherein R is R.sub.1, R.sub.1O--, R.sub.1R.sub.2N--, or R.sub.1S--,
R.sub.1 is hydrocarbyl, heterosubstituted hydrocarbyl, or
heterocyclo, and R.sub.2 is hydrogen, hydrocarbyl or substituted
hydrocarbyl.
[0087] The term "acetal," as used herein, refers to a moiety in
which two bonded oxygens are to the same carbon; one of the other R
groups of an acetal carbon is hydrogen.
[0088] The term "acyloxy," as used herein alone or as part of
another group, denotes an acyl group as described above bonded
through an oxygen linkage (O), e.g., RC(O)O-- wherein R is as
defined in connection with the term "acyl."
[0089] The term "alkyl" as used herein describes groups which are
preferably lower alkyl containing from one to eight carbon atoms in
the principal chain and up to 20 carbon atoms. They may be straight
or branched chain or cyclic and include methyl, ethyl, propyl,
isopropyl, butyl, hexyl and the like.
[0090] The term "alkaryl" or "alkylaryl" as used herein describes
groups which are preferably aryl groups having a lower alkyl
substituent, such as toluyl, ethylphenyl, or methylnapthyl.
[0091] The term "alkenyl" as used herein describes groups which are
preferably lower alkenyl containing from two to eight carbon atoms
in the principal chain and up to 20 carbon atoms. They may be
straight or branched chain or cyclic and include ethenyl, propenyl,
isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
[0092] The term "alkynyl" as used herein describes groups which are
preferably lower alkynyl containing from two to eight carbon atoms
in the principal chain and up to 20 carbon atoms. They may be
straight or branched chain and include ethynyl, propynyl, butynyl,
isobutynyl, hexynyl, and the like.
[0093] The term "aralkyl" as used herein describes groups which are
preferably lower alkyl containing from one to eight carbon atoms
having an aryl substituent, such as benzyl, phenylethyl, or
2-napthylmethyl.
[0094] The term "aromatic" as used herein alone or as part of
another group denotes optionally substituted homo- or heterocyclic
aromatic groups. These aromatic groups are preferably monocyclic,
bicyclic, or tricyclic groups containing from 6 to 14 atoms in the
ring portion. The term "aromatic" encompasses the "aryl" and
"heteroaryl" groups defined below.
[0095] The term "aryl" as used herein alone or as part of another
group denote optionally substituted homocyclic aromatic groups,
preferably monocyclic or bicyclic groups containing from 6 to 12
carbons in the ring portion, such as phenyl, biphenyl, naphthyl,
substituted phenyl, substituted biphenyl or substituted naphthyl.
Phenyl and substituted phenyl are the more preferred aryl.
[0096] The term "ether," as used herein, denotes an oxygen atom
connected to two alkyl, aryl, substituted alkyl, or substituted
aryl groups, i.e., of the general formula ROR'.
[0097] The terms "halogen" or "halo" as used herein alone or as
part of another group refer to chlorine, bromine, fluorine, and
iodine atoms.
[0098] The term "heteroatom" refers to atoms other than carbon and
hydrogen.
[0099] The terms "heterocyclo" or "heterocyclic" as used herein
alone or as part of another group denote optionally substituted,
fully saturated or unsaturated, monocyclic or bicyclic, aromatic or
non-aromatic groups having at least one heteroatom in at least one
ring, and preferably 5 or 6 atoms in each ring. The heterocyclo
group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen
atoms in the ring, and is bonded to the remainder of the molecule
through a carbon or heteroatom. Exemplary heterocyclo groups
include heteroaromatics as described below. Exemplary substituents
include one or more of the following groups: hydrocarbyl,
substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy,
alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano,
ketals, acetals, esters and ethers.
[0100] The term "heteroaryl" as used herein alone or as part of
another group denote optionally substituted aromatic groups having
at least one heteroatom in at least one ring, and preferably 5 or 6
atoms in each ring. The heteroaryl group preferably has 1 or 2
oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is
bonded to the remainder of the molecule through a carbon. Exemplary
heteroaryls include furyl, benzofuryl, oxazolyl, isoxazolyl,
oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl,
indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl,
purinyl, quinolinyl, isoquinolinyl, imidazopyridyl and the like.
Exemplary substituents include one or more of the following groups:
hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy,
acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido,
amino, cyano, ketals, acetals, esters and ethers.
[0101] The terms "hydrocarbon" and "hydrocarbyl" as used herein
describe organic compounds or radicals consisting exclusively of
the elements carbon and hydrogen. These moieties include alkyl,
alkenyl, alkynyl, and aryl moieties. These moieties also include
alkyl, alkenyl, alkynyl, and aryl moieties substituted with other
aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl
and alkynaryl. Unless otherwise indicated, these moieties
preferably comprise 1 to 20 carbon atoms.
[0102] The "substituted hydrocarbyl" moieties described herein are
hydrocarbyl moieties which are substituted with at least one atom
other than carbon, including moieties in which a carbon chain atom
is substituted with a hetero atom such as nitrogen, oxygen,
silicon, phosphorous, boron, sulfur, or a halogen atom. These
substituents include halogen, heterocyclo, alkoxy, alkenoxy,
aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino,
amido, nitro, cyano, ketals, acetals, esters and ethers.
[0103] The terms "oxygen protecting group" as used herein denote a
group capable of protecting a free oxygen atom (i.e., the oxygen of
a hydroxyl group) that, subsequent to the reaction for which
protection is employed, may be removed without disturbing the
remainder of the molecule.
[0104] The term "silyl ether," as used herein, denotes a moiety in
which a silicon atom is covalently bonded to an alkoxy group. The
general structure is R.sup.1R.sup.2R.sup.3Si--O--R.sup.4, wherein
R.sup.4 is an alkyl group or an aryl group, and R.sup.1-R.sup.3 are
independently hydrocarbyl or substituted hydrocarbyl.
[0105] When introducing elements of the present invention or the
preferred embodiments(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0106] As various changes could be made in the above compounds,
products and methods without departing from the scope of the
invention, it is intended that all matter contained in the above
description and in the examples given below, shall be interpreted
as illustrative and not in a limiting sense.
EXAMPLES
[0107] The following examples illustrate various iterations of the
invention.
Example 1
Reaction of Oripavine with Ethyl Chloroformate
[0108] Oripavine was reacted with three different concentrations of
ethyl chloroformate (ClCO.sub.2Et). Three samples of oripavine were
prepared. For each, 0.3 g of oripavine was added to 5 mL of
chloroform (CHCl.sub.3) with stirring. Once in solution, the
mixtures were cooled to about 0-5.degree. C. Five mL of saturated
NaHCO.sub.3 was added with stirring to each mixture. A different
amount of ClCO.sub.2Et was added to each mixture, i.e., 1, 2 or 3
equivalents of ClCO.sub.2Et (as shown in Table 1). Each mixture was
stirred for 30 minutes at room temperature after addition of the
ethyl chloroformate and then sampled for HPLC to determine if the
reaction has gone to completion.
TABLE-US-00001 TABLE 1 Oripavine Reaction. Sample # ClCO.sub.2Et
Result 1 95 .mu.L Reaction not complete 2 2 .times. 95 .mu.L
Reaction not complete 3 3 .times. 95 .mu.L Reaction complete
[0109] As shown in Table 1, the reaction was complete when
oripavine was reacted with three equivalents of ClCO.sub.2Et
(sample #3). For this sample, the organic solution was washed with
5% NaHCO.sub.3 (9 mL), 5% HOAc (9 mL), and then water (9 mL). The
organic layer was reduced to dryness under a partial vacuum to give
0.4 g of solid.
Example 2
Reaction of Thebaine with Ethyl Chloroformate
[0110] To determine the correct ratio for thebaine and ethyl
chloroformate an experiment similar to that described in Example 1
was performed. For each sample, 0.31 g of thebaine was dissolved in
5 mL of CHCl.sub.3. Once in solution, the mixtures were cooled to
about 0-5.degree. C. Five mL of saturated NaHCO.sub.3 was added
with stirring to each mixture. ClCO.sub.2Et (as shown in Table 2)
was added to each mixture, which were stirred for 30 minutes at
room temperature and then sampled for HPLC to determine if the
reaction has gone to completion.
TABLE-US-00002 TABLE 2 Thebaine Reaction. Sample # ClCO.sub.2Et
Result 1 95 .mu.L Reaction not complete 2 2 .times. 95 .mu.L
Reaction not complete 3 3 .times. 95 .mu.L Reaction complete
[0111] As shown in Table 2, the reaction was complete when thebaine
was reacted with three equivalents of ClCO.sub.2Et (sample #3).
This sample was washed with 5% NaHCO.sub.3), 5% HOAc, and water as
described above. The organic layer was reduced to dryness under a
partial vacuum to give 0.4 g of solid.
* * * * *